DE3826439C2 - Sulfonamidothienylcarbonsäureverbindungen - Google Patents

Description

The invention relates to new sulfonamidothienylcarboxylic acid ver bonds. These new compounds can act as thromboxanes receptor antagonists can be used.

The published patent application DE 36 29 929 A1 describes sulfonamido-ethyl compounds, processes for their preparation and pharmaceutical compositions containing these compounds. The Compounds have valuable pharmacological properties, in particular antithrombotic effects, and are also thromboxane antagonists.

The invention relates to compounds of general formula I.

in which X is a halogen atom, a lower alkyl, arylalkyl or alkoxy radical or a hydroxyl group, the phenyl ring being mono- or disubstituted, R '-COOH or one of the following radicals

where R "is lower alkyl or aryl and n and m are independently 1 or 2. The compounds of the invention are potent thromboxane A ₂ receptor antagonists.

The terms "lower alkyl group" or "alkyl group" denote unbranched or branched residues with up to 12 Koh lenstoffatomen, preferably 1 to 8 carbon atoms, such as  the methyl, ethyl, propyl, isopropyl, butyl, tert-Bu tyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- Dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, Decyl, undecyl, and dodecyl group, the various ver branched chain isomers thereof and also such groups a halogen substituent, such as a fluorine, bromine, chlorine or iodine atom or a trifluoromethyl group, an alkoxy, Halogenaryl, cycloalkyl (namely cycloalkylalkyl) or Alkylcycloalkyl.

The term "aryl group" refers to monocyclic or bicyclic aromatic radicals with 6 to 10 carbon atoms in the Ring portion, such as the phenyl, naphthyl, substituted phenyl or substituted naphthyl group, the phenyl or Naphthyl group at least one lower alkyl radical, a halogen atom (Chlorine, bromine or fluorine) or a lower alkoxy radical as May contain substituents.

The term "aralkyl radical" refers to lower alkyl radicals above description, which has an aryl substituent point like the benzyl group.

The term "alkoxy radical" denotes the one described above benen lower alkyl radicals, bonded to an oxygen atom.

In preferred compounds of the formula I, m has the value 1 and n is 1 or 2 or m is 2 and n is 1 and R 'is COOH and X is a chlorine atom, with the proviso that when n is 1 and R 'is -COOH, X is not a halogen atom, not a methyl group and / or is not a methoxy group.

The various compounds of the invention can be as described below.

A suspension of an amine of formula II

and anhydrous sodium acetate in ethanol is a solution of an arylsulfonyl chloride in ethanol to a sulfonamide compound of formula III

implemented.

The compound of formula III and an unbranched alkanoyl chloride are dissolved in dry benzene and cooled to 0 ° C. Anhydrous tin chloride is added to this solution at 0 ° C and it becomes a compound of formula IV

receive. A compound of formula IV in which the alkyl radical is a methyl group is dissolved in a mixture of methanol and perchloric acid to which thallium (III) nitrate is added. The compound of formula V

will get. The hydrolysis of the methyl ester of the formula V by a process known in the art (KOH, H ₂ O, MeOH) leads to a compound of the formula VI

Alternatively, compounds of formula IA, in which R 'COOH is obtained by using a compound of formula IV Sulfur and morpholine is heated, then with a strong base such as KOH is hydrolyzed and then acidified.

Compounds of the formula I in which m has a value greater than 1 can alternatively be prepared as follows:
A compound of formula VI is first in hot benzene with thionyl chloride to a compound of structure VII

implemented. The connection of structure VII is then in one Mixture of inert organic solvents, such as ether or Tetrahydrofuran reacted with a solution of diazomethane. To the concentration under reduced pressure becomes a compound of Get Formula VIII.

Compounds of structure VIII are then made by heating converted into compounds of the structure IB, where in Presence of metallic silver or a silver (I) salt, like silver (I) oxide in a little water a compound of For mel IB receives in which R 'COOH is while one is in the presence an alkanol receives a compound of formula IB in which R 'is COOalkyl.

Compounds of formula IB in which R 'is COOalkyl can by the hydrolysis in compounds described above of the formula I in which R 'is COOH. The The method described above can be used to manufacture Compounds of formula I are repeated, in which m is one has a value greater than 2.

In the case of the compounds of formula I in which X is a hydroxyl group, the methods described above can be used provided that the hydroxyl group of the arylsulfonyl halide has been protected beforehand, with customary protective groups such as

be used. Thus, a protected arylsulfonyl halide, such as a compound of formula IX

with compounds of formula II as described above, to compounds of formula X

implement. Compounds of formula X are then as described above to compounds of formula XI

converted, of which then using standard procedures the protective group is removed, compounds of the formula I can be obtained in which X is a hydroxyl group.

Compounds of formula I in which R 'is a 5-tetrazolyl group can be prepared by using compounds of the formula I in which R 'is COOH, in the usual way in compounds of For mel I, in which R 'is CN, are converted and then with an inorganic azide such as ammonium azide in an organic Solvents such as dimethylformamide are reacted.

Compounds of formula I in which R 'is the rest

is, are prepared by compounds of the formula I in which R 'is COOH, first with thionyl chloride in organic solvents, such as benzene or tetrahydrofuran and then with a sulfonamide of the formula

R "-SO ₂ NH ₂

in the presence of an organic base such as pyridine or tri ethylamine, or in the presence of an inorganic base, such as Na trium bicarbonate or potassium carbonate.

The compounds of the invention are drugs with an effect on the cardiovascular system and the lungs. They are suitable for inhibition platelet aggregation, for example to inhibit arachidone acid-induced platelet aggregation, e.g. B. at Be treatment of thrombosis, such as the coronary or cerebral thrombus evil. They are also suitable for the inhibition of bronchial constrictions.

They are selective thromboxane A ₂ receptor antagonists, ie they have a vasodilatory effect and are therefore suitable for the treatment of ischemic diseases of the heart muscle such as angina pectoris.

The compounds of the invention can also be used together with Cyclic AMP phosphodiesterrase (PDE) inhibitor, such as Theophylline or papaverine for the production and storage of Platelet concentrates are used.

The compounds of the invention can be oral or parenteral to mammals, such as humans, cats or administered to the dog, which is known to sol diseases. The connections of the Erfin can be used in an effective amount within the Do range of about 0.1 to 100 mg / kg, preferably from about 1 to 50 mg / kg and particularly preferably from about 2 up to 25 mg / kg, either in one dose per day or divided into 2 to 4 doses per day.

The active ingredient can be in a composition such as a Ta blette, capsule, solution or suspension can be used about 5 to about 500 mg per unit dose of a compound of formula I or a mixture of the compounds of For mel I contains. The compounds of the invention can in usual type with a physiologically compatible carrier,  Excipient, binder, preservative, stabilizer, Flavoring etc. are made up. The connections The invention can also be used as a cream or ointment for treatment administration of peripheral vascular diseases locally be enough.

The examples below show preferred embodiments form the invention. Unless otherwise stated, will be all temperatures expressed in ° C.

example 1 5- (2 - (((4-chlorophenyl) sulfonyl) amino) ethyl) -2-thiophenes sigsäure A. N- (2- (Thien-2-yl) ethyl) -4-chlorobenzenesulfonamide

To a suspension of 1.118 g (8.79 mmol) of 2- (thien-2-yl) - ethylamine and 1.44 g (17.6 mmol) of anhydrous sodium acetate in 6 ml of 100 percent ethanol dropwise a solution of 1.86 g (8.79 mmol) of 4-chlorobenzenesulfonyl chloride in 20 ml Given 100 percent ethanol. The reaction mixture is Stirred for 30 minutes. Three additional 100 mg servings Sulfonyl chloride is added at 20 minute intervals, until the reaction is complete. After another 5 minutes the reaction mixture is under reduced pressure concentrated. The residue is taken up in 5 ml of water and brought to pH 3 by 6N HCl. The mixture is extracted with three 50 ml portions of ether. The combined organic phases are made using Dried sodium sulfate and under reduced pressure concentrated. The residue is then acetic acid Add 5 ml of toluene and then evaporate under reduced pressure. There are 2.56 g (97%) Rohpro product obtained as a yellow solid.  

B. N- (2- (5-acetylthien-2-yl) ethyl) - (4-chlorobenzene) sul fonamid

2.36 g (7.82 mmol) of the product from Part A and 0.67 ml (9.38 mmol) Acetyl chloride are dissolved in dry benzene and cooled to 0 ° C. The cold solution quickly becomes 0.92 ml (7.82 mmol) of anhydrous stannous chloride. Tougher Orange-black precipitation forms and complicates the stirring. The cold water bath is removed and the never crushed the blow with a spatula. The mixture turns 20 Stirred minutes and then quenched with 10 ml of 2N HCl. 25 ml Ether is added to dissolve the remaining solids ben. The layers are separated and the aqueous phase is extracted twice with 25 ml ether. The united or ganic layers are washed with water and then with Extracted 25 ml of 2N NaOH. Oil settles in the separating screed ter. This oil and the aqueous phase are removed and the organic phase is extra with a further 25 ml of 2N NaOH hiert. The organic phase contains only a little N-acylated Product. Therefore, the organic phase is reduced Concentrated pressure. The residue is ge in 10 ml of methanol dissolves and 4 ml of 2 N NaOH are added. After 10 minutes Standing the hydrolysis is complete and the mixture is concentrated under reduced pressure. The backlog and the Basic extracts obtained above are treated with 6 N HCl acidified to pH 1. The mixture obtained is extracted three times with 40 ml of methylene chloride. The unite th organic extracts are using Dried sodium sulfate and kon under reduced pressure centered. The residue is in a minimum amount of Me Dissolved ethylene chloride and by flash chromatography on 20 cm × 50 mm silica cleaned by using 50% ethyl acetate Hexane is eluted. Yield: 2.15 g (80%) yellowish solid material.  

C. Methyl 5- (2 - (((4-chlorophenyl) sulfonyl) amino) ethyl) -2- thiophenacetat

2.15 g (6.25 mmol) of the product from Part B are mixed in one Mixture of 90 ml of methanol and 5 ml of 70 percent perchlor acid, to which 3.06 g (6.88 mmol) of thallium (III) nitrate trihy be given resolved. After stirring for 16 hours the mixture is filtered. The solids are mixed with methanol washed and the combined filtrate and wash solutions are concentrated to about 30 ml under reduced pressure. This mixture is diluted with 100 ml of water and three times extracted with 75 ml of methylene chloride. The united organization African phases are ge using sodium sulfate dries and concentrated under reduced pressure. The The residue is removed by flash chromatography on 15 cm × 50 ml Purified silica by eluting with 35% ethyl acetate-hexane is. Yield: 2.14 g (91%) of a yellowish solid F. 41 to 42.5 ° C.

D. 5- (2 - (((4-Chlorophenyl) sulfonyl) amino) ethyl) -2-thio phenessigsäure

500 mg (1.34 mmol) of the product from Part C are dissolved in 5 ml of methanol. 2 ml of 2N KOH are added to this solution and the temporarily yellow solution is stirred for 2 hours. The mixture is concentrated under reduced pressure. 5 ml of water are added to the residue. The mixture is acidified to pH 2 with 6N HCl. The solid is collected by filtration, washed with 5 ml of water and dried under reduced pressure. Yield: 472 mg (98%) white solid. After recrystallization from ethyl acetate-hexane, 398 mg of fine white platelets with a melting point of 137.5 to 138.5 ° C. are obtained.
Analysis for C ₁₄ H ₁₄ NO ₄ S ₂ Cl
Calculated:
C 46.73; H 3.92; N 3.89; S 17.82; Cl 9.85;
Found:
C 46.71; H 3.94; N 3.82; S 17.49; Cl 9.94.

Example 2 (5- (3 - (((4-chlorophenyl) sulfonyl) amino) -propylthien-2-yl) - acetic acid A. 2- (2-bromoethyl) thiophene

To a solution of 5.0 g (39.0 mmol) of 2- (2-thienyl) ethanol in 100 ml of carbon tetrachloride which is at a temperature of 65 ° C., 4.4 ml (46.8 mmol) of phosphorus (III ) -bromide given. After stirring for 20 minutes, the reaction mixture is cooled to room temperature and poured onto about 100 g of ice. The organic layer is separated. The aqueous layer is extracted three times with 50 ml of methylene chloride. The four combined organic layers are washed with 50 ml saturated NaHCO ₃ , dried using Na ₂ SO ₄ and concentrated under reduced pressure to a volume of approx. 50 ml. The residue is first distilled to remove the solvent at ambient pressure and then distilled under reduced pressure. 3.76 g (50%) of the desired title compound are obtained as a transparent water-colored liquid.

B. 3- (Thien-2-yl) propionitrile

A solution of 3.83 g (58.9 mmol) of potassium cyanide dissolved in 3 ml of water is added to a solution of 3.75 g (19.6 mmol) of the compound from Part A in 20 ml of 95% ethanol. The mixture is then heated under reflux for 2 1/2 hours and then cooled. Most of the alcohol is removed under reduced pressure. The residue is partitioned between 50 ml of ether and an equal volume of water. The aqueous phase is extracted with 50 ml of ether. The combined organic layers are dried using Na ₂ SO ₄ and concentrated under reduced pressure. After distilling the residue under reduced pressure, 2.30 g (86%) of a transparent water-colored liquid are obtained.

C. 3- (Thien-2-yl) propylamine

50 ml ether are slowly added to 0.972 g (7.29 mmol) aluminum (III) chloride at 0 ° C. 0.277 g (7.29 mmol) of lithium aluminum hydride is added to this solution in portions. A solution of 1.0 g (7.29 mmol) of the compound from Part B dissolved in 5 ml of ether is then added dropwise to this solution. After stirring for 10 minutes, 10 ml of water are slowly added to the reaction mixture. The mixture is adjusted to pH 10 by adding 19 NNaOH. The layers are separated and the organic layer is extracted three times with 50 ml ether. The combined organic layers are dried using Na ₂ SO ₄ and concentrated under reduced pressure. After distillation from flask to flask, 919.5 mg (89%) of a transparent water-colored liquid with a boiling point of 130 ° C (bath temperature) are obtained.

D. N- (3- (Thien-2-yl) propyl) -4-chlorobenzenesulfonamide

To 500 mg (3.54 mmol) of the amine from Part C and 581 mg (7.08 mmol) of sodium acetate in 15 ml of 100 percent ethanol are added dropwise 971 mg (4.60 mmol) of 4-chlorobenzenesulfonyl chloride dissolved in 20 ml of ethanol. After stirring for 20 minutes, the reaction mixture is filtered. The solids are washed with ethanol and the combined filtrates are concentrated under reduced pressure. The residue is diluted with 15 ml of water and adjusted to a pH of 10 by 2 N NaOH. The solution is extracted twice with 30 ml of methylene chloride. The combined organic layers are dried using Na ₂ SO ₄ and concentrated under reduced pressure. Yield: 1.10 g (98%) solid.

E. N- (3- (5-acetylthien-2-yl) propyl) -4-chlorobenzenesul fonamid

To a 0 ° C cold solution of 0.322 ml (4.53 mmol) of the sulfonamide from part D and acetyl chloride in 10 ml of benzene, 0.42 ml (3.66 mmol) of tin (IV) chloride are added at once with mechanical stirring given. The reaction mixture now containing an orange precipitate is warmed to room temperature. Then 0.322 ml (4.53 mmol) of acetyl chloride are added. After 20 minutes, the blue reaction mixture is quenched with 15 ml of water. After all solids have been dissolved, the layers are separated. The aqueous layer is extracted twice with 25 ml of methylene chloride. The combined organic layers are dried using Na ₂ SO ₄ and concentrated under reduced pressure. The residue is dissolved in 10 ml of methanol and then 3 ml of 0.25 M potassium carbonate in 4/1 methanol / water are added. After 30 minutes, the reaction mixture is concentrated under reduced pressure. The residue is acidified with 1N HCl to a pH of about 1 and then extracted three times with 20 ml of methylene chloride. The combined organic layers are dried using Na ₂ SO ₄ and concentrated under reduced pressure. After this basic hydrolysis, thin layer chromatography (TLC, R _f 0.09, silica, 25% ethyl acetate-hexane) shows that no N-acylated product is present. Product yield: 1.21 g (97%).

F. Methyl- (5- (3 - (((4-chlorophenyl) sulfonyl) amino) propyl) - thien-2-yl) acetate

Approximately 3.38 mmol of the ketone from Part E is dissolved in 10 ml of methanol. 1.7 ml of 70 percent perchloric acid and 1.80 g (4.06 mmol) of thalium (III) nitrate trihydrate are successively added to this solution. After stirring for 21 hours, the reaction mixture is filtered and the solids are washed with methanol. The combined filtrates are poured into 20 ml of water and extracted four times with 20 ml of methylene chloride. The combined organic layers are dried using Na ₂ SO ₄ and concentrated to a brown oil under reduced pressure. The oil obtained is purified by flash chromatography on 37 mm × 15 cm silica, eluting with 40% ethyl acetate-hexane.
Yield: 760 mg (58%) colorless solid.

G. (5- (3 - (((4-chlorophenyl) sulfonyl) amino) propyl) thien - 2-yl) acetic acid

760 mg (1.96 mmol) of the ester from Part F are dissolved in 20 ml of methanol. 6 ml of 2N KOH are added to the solution. After standing for 1 1/2 hours, the methanol is removed under reduced pressure. 20 ml of water and then 1N HCl are added to the residue, which sets the pH to 1.5. The precipitated solid is collected by filtration, washed with water and air dried. After recrystallization from ethyl acetate-hexane, 565 mg (77%) of white crystals of mp 134.5 to 135 ° C. are obtained.
Analysis for C ₁₅ H ₁₆ CINO ₄ S ₂ :
Calculated:
C 48.19; H 4.31; N 3.75; Cl 9.48; S 17.15;
Found:
C 48.03; H 4.35; N 3.73; Cl 9.89; S 17.30.

Example 3 3- (5- (2 - (((4-chlorophenyl) sulfonyl) amino) ethyl) thien-2- yl) propionic acid A. Methyl-3- (5- (2 - (((4-chlorophenyl) sulfonyl) amino) - ethyl) thien-2-yl) propionate

A solution of 500 mg (1.40 mmol) of the title compound of Example 2 in about 1 ml of thionyl chloride is under for 20 minutes Heated to reflux. The excess thionyl chloride is then removed by distillation under slightly reduced pressure.  Then 4 ml of benzene are added and it is subsequently distilled to remove thionyl chloride. The residue is dried under reduced pressure. The the solid obtained is dissolved in about 5 ml of ether, the one contains a small amount of THF. This solution is at 0 ° C dropwise to about 12 ml (about 0.3 M) dissolved in ether Given diazomethane. Then another 6 ml of diazo added methane solution to decrease the formation of the diazoketone conclude. After 5 minutes the solvent is added under ver reduced pressure removed. The residue is dissolved in 20 ml metha nol taken up and heated to 60 ° C. Servings of each approx. 40 mg silver (I) oxide are added every 15 minutes given the hot solution. After 11/2 hours the Ge mixed with Norit and filtered through diatomaceous earth. The The filtrate is concentrated under reduced pressure. The The residue is then taken up in methylene chloride and passed through a short plug of silica, in which is eluted with 1: 1 methylene chloride / ethyl acetate. The Eluate becomes 399 mg of a solid under reduced pressure concentrated. This material comes with 126 mg of a material from a previous approach Flash chromatography purified on 25 mm × 15 cm silica, by eluting with 40% ethyl acetate-hexane. There will be 357 mg (47% yield) of a white solid.

B. 3- (5- (2 - (((4-Chlorophenyl) sulfonyl) amino) ethyl) thien - 2-yl) propionic acid

The ester of Part A is hydrolyzed by dissolving it in 10 ml of methanol and stirring for 1 1/2 hours after adding 2 ml of 2N KOH. The reaction mixture is then concentrated under reduced pressure. The residue is acidified to pH 2 with 1N HCl. The precipitated solid is collected by filtration, washed with water and then air dried. After recrystallization from ethyl acetate-hexane, 257.3 mg (75% yield) of yellow crystals of mp 131 to 132 ° C. are obtained. A second crop of 33 mg (10% yield) of mp 127 to 129.5 ° C. is obtained from the mother liquors.
Analysis for C ₁₅ H ₁₆ ClNO ₄ S ₂
Calculated:
C 48.19; H 4.31; N 3.75; Cl 9.48; S 17.15;
Found:
C 48.25; H 4.26; N 3.67; Cl 9.63; S 16.85.

Claims (2)

1. Compounds of formula I.
in which X represents a halogen atom, a lower alkyl, arylalkyl or alkoxy radical or a hydroxyl group, where the phenyl ring is mono- or disubstituted, R '-COOH or one of the following radicals
means, where R "represents a lower alkyl or aryl radical and n and m independently of one another have the value 1 or 2, wherein each lower alkyl radical is an unbranched or branched radical having 1 to 8 carbon atoms, aryl radical is a monocyclic or bicyclic aromatic radical having 6 to 10 carbon atoms in the ring part, aralkyl radical means a lower alkyl radical as defined above which has an aryl substituent as defined above, and alkoxy radical means a lower alkyl radical as defined above which is bonded to an oxygen atom, with the proviso that when n is 1 and R '- Is COOH, X is not a halogen atom, not a methyl group and / or not a methoxy group. 2. (5- (3 - (((4-Chlorophenyl) sulfonyl) amino) propyl) thien-2-yl) acetic acid.